Cm. Crews et al., GTP-DEPENDENT FINDING OF THE ANTIPROLIFERATIVE AGENT DIDEMNIN TO ELONGATION-FACTOR 1-ALPHA, The Journal of biological chemistry, 269(22), 1994, pp. 15411-15414
The marine natural product, didemnin B, is a 7-amino acid, cyclic deps
ipeptide that inhibits G(1) cell cycle progression at nanomolar concen
trations by undefined mechanisms. It has been reported to exhibit immu
nosuppressive activities in animals and is undergoing clinical trials
as a potential antineoplastic drug. In addition, at higher concentrati
ons, didemnin B has been shown to inhibit in vivo and in vitro protein
synthesis. However, the mechanisms by which inhibition is achieved ar
e unknown. To investigate didemnin's various modes of action, an affin
ity column was synthesized and used to purify didemnin-binding protein
s. The major retained protein was the 49-kDa guanine nucleotide-bindin
g elongation factor, EF-1 alpha, which was identified by peptide seque
nce analysis, Moreover, didemnin binds EF-1 alpha only in the presence
of GTP but does not inhibit the GTPase activity of EF-1 alpha. Theref
ore, EF-1 alpha is likely to be the intracellular target responsible f
or didemnin B's ability to inhibit protein synthesis. Furthermore, thi
s specificity of didemnin affinity for the GTP-bound conformation of a
guanine nucleotide-binding protein with homology to the Ras superfami
ly suggests a possible mode of action for didemnin's antiproliferative
activity.